As the resident dendritic cells of mammalian epidermis, Langerhans' cells (LC) function as sentinels capable of initiating immune responses that protect the skin against infectious agents and cancer. In order to do so, LC take up and process foreign antigens within the epidermis prior to migrating to draining lymph nodes where they present these antigens to thymus derived lymphocytes. To maintain LC levels within the epidermis, these cells must be replenished from CD34+ precursors that enter the skin from the peripheral blood. Unfortunately, most of what is known about the development of LC comes from in vitro studies that may or may not be relevant to what occurs within the intact organism. However, the small amount of in vivo evidence that exists, suggests that requirements for the development of LC are unique as compared to those for other types of dendritic cells. The purpose of this study is to assess the role of cytokines/chemokines in this replenishment process in vivo. This will be done by analyzing the rate of recovery of LC and their phenotype in cytokine/chemokine gene knockout and transgenic mice following depletion of LC by topical LPS application. The results of these studies will likely improve our ability to modulate immune responses at their earliest phases by controlling LC development.